Type 2 diabetes (T2D) is the most common chronic disease affecting human health. Recent longitudinal and genome-wide association studies provide strong evidence that the ability of pancreatic ?-cells to fulfill insulin demand through development, growth, survival, and function is a key determinant of whether an individual will develop T2D ! under various nutrient conditions. However, there are no effective clinical treatments that target ?-cell growth and maintenance of their differentiated identity as insulin producing-cells. We propose that OGT (O-GlcNAc Transferase), a nutrient-sensor expressed at a very high level in ?-cells, has key developmental regulatory properties and the ability to integrate signaling networks to regulate ?-cell plasticity in response to insulin demand and nutrient stress. OGT is the sole enzyme adding a single O-GlcNAc post-translational modification (O-GlcNAcylation) onto proteins to orchestrate and fine-tune glucose metabolism, and ?-cell growth and maintenance of identity under stress responses to nutrient changes and hormonal cues. We hypothesize that OGT tightly controls the O-GlcNAcylation state of downstream targets, including Pdx1, to promote ?-cell development and function. Thus, our long-term goal is to define the mechanisms of how OGT integrates signaling networks impinging on ?-cell plasticity (development and identity) to promote functional ?-cells. We will test our hypothesis with the following Aims: 1. To establish the molecular mechanisms of how OGT regulates ?-cell development and mass. 2. To delineate the mechanisms of how OGT regulates ?-cell mass and identity under metabolic stress. The impact of this grant will show the central role of OGT in ?-cell development and mass maintenance, and illustrate the translational relevance of OGT during time windows critical to metabolic health . Finally, these results will advance the field of ?-cell biology and will open new horizons for therapies for patients with diabetes.